Rufo P A, Jiang L, Moe S J, Brugnara C, Alper S L, Lencer W I
Combined Program in Pediatric Gastroenterology and Nutrition, Children's Hospital, Boston, Massachusetts 02115, USA.
J Clin Invest. 1996 Nov 1;98(9):2066-75. doi: 10.1172/JCI119012.
Clotrimazole (CLT) prevents dehydration of the human HbSS red cell through inhibition of Ca++-dependent (Gardos) K+ channels in vitro (1993. J. Clin Invest. 92:520-526.) and in patients (1996. J. Clin Invest. 97:1227-1234.). Basolateral membrane K+ channels of intestinal crypt epithelial cells also participate in secretagogue-stimulated Cl- secretion. We examined the ability of CLT to block intestinal Cl- secretion by inhibition of K+ transport. Cl- secretion was measured as short-circuit current (Isc) across monolayers of T84 cells. CLT reversibly inhibited Cl- secretory responses to both cAMP- and Ca2+-dependent agonists with IC50 values of approximately 5 microM. Onset of inhibition was more rapid when CLT was applied to the basolateral cell surface. Apical Cl- channel and basolateral NaK2Cl cotransporter activities were unaffected by CLT treatment as assessed by isotopic flux measurement. In contrast, CLT strongly inhibited basolateral 86Rb efflux. These data provide evidence that CLT reversibly inhibits Cl- secretion elicited by cAMP-, cGMP-, or Ca2+-dependent agonists in T84 cells. CLT acts distal to the generation of cAMP and Ca2+ signals, and appears to inhibit basolateral K+ channels directly. CLT and related drugs may serve as novel antidiarrheal agents in humans and animals.
克霉唑（CLT）在体外（1993年《临床研究杂志》92:520 - 526）和患者体内（1996年《临床研究杂志》97:1227 - 1234）通过抑制钙依赖性（加尔多斯）钾通道来防止人HbSS红细胞脱水。肠隐窝上皮细胞的基底外侧膜钾通道也参与促分泌剂刺激的氯离子分泌。我们研究了CLT通过抑制钾转运来阻断肠道氯离子分泌的能力。氯离子分泌通过测量跨T84细胞单层的短路电流（Isc）来测定。CLT可逆地抑制对cAMP和钙依赖性激动剂的氯离子分泌反应，IC50值约为5微摩尔。当将CLT应用于基底外侧细胞表面时，抑制的起始更快。通过同位素通量测量评估，顶端氯离子通道和基底外侧NaK2Cl共转运体活性不受CLT处理的影响。相反，CLT强烈抑制基底外侧86Rb外流。这些数据提供了证据表明CLT可逆地抑制T84细胞中由cAMP、cGMP或钙依赖性激动剂引发的氯离子分泌。CLT作用于cAMP和钙信号产生的下游，并且似乎直接抑制基底外侧钾通道。CLT及相关药物可能作为人和动物新型止泻剂。
